Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver diseases, ranging from simple steatosis (fat in the liver) to non-alcoholic steatohepatitis (NASH) to cirrhosis. According to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), it is the most common form of chronic liver disease and with the risk factors of obesity, diabetes, and metabolic syndrome on the rise, the prevalence of NAFLD is also expected to increase. While the role of oxidative stress in NAFLD is accepted, what is not known is the effectiveness of reducing oxidative stress in preclinical models of NAFLD. Without this knowledge, we cannot determine the utility of novel classes of high- potency antioxidants as potential therapeutics for NAFLD damage. To develop antioxidants for NAFLD that exhibit potent antioxidant activity, that do not pass radicals on to other molecules and that can be targeted, we have turned to nanotechnology. These nano-antioxidants, polyethylene glycolated hydrophilic carbon clusters (PEG-HCCs), are based on carbon nano structures that have conjugated ring structures so that they act as terminal oxidant acceptors or radical sponges. We have also demonstrated that these PEG-HCCs can be targeted to specific cell types (manuscript in preparation). Our long term goal is to understand the mechanisms of reactive oxygen species (ROS) in NAFLD pathology in order to develop effective therapeutics that can prevent and potentially reverse damage due to oxidative stress. Our objective is to determine the effect of reducing ROS through high-efficiency novel antioxidant compounds on the development of NAFLD pathology by in vivo imaging, biochemistry and histopathology in mouse models of NAFLD. Our central hypothesis is that reducing ROS will improve liver function, reduce liver damage and oxidative stress in mouse models of NAFLD. The rationale for the proposed work is that a mechanistic understanding of oxidative stress on NAFLD pathologies will lay the foundation for viable therapeutic approaches. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because we are conducting research that will advance our understanding of the role of oxidative stress in the development of non-alcoholic fatty liver disease (NAFLD). As a result, the proposed work is relevant to the component of NIH's mission of developing novel and innovative methods to treat NAFLD, a disease that is on the rise and has significant health consequences.